The invention relates to new polycyclic azaindole compounds. The compounds of the present invention are new and have very valuable pharmacological characteristics in respect of melatoninergic receptors.
The prior art describes polycyclic azaindole compounds for use in synthesis (Heterocycles, 41 (9), 1995, pp. 1987-98; Tetrahedron Letters, 26 (10), 1985, pp. 1295-6) or as anti-tumour and antiviral agents (Tetrahedron, 50 (13), 1994, pp. 3987-92).
Numerous studies in the last ten years have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. Its half-like is quite short, however, owing to the fact that it is rapidly metabolised. Great interest therefore lies in the possibility of providing the clinician with melatonin analogues that are metabolically more stable, have an agonist or antagonist character and that may be expected to have a therapeutic effect that is superior to that of the hormone itself.
In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep disorders (Psychopharmacology. 1990, 100, pp. 222-226), ligands of the melatoninergic system have valuable pharmacological properties in respect of the central nervous system, especially anxiolytic and antipsychotic properties (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and analgesic properties (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson""s disease (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer""s disease (Brain Research, 1990, 528, pp. 170-174). Those compounds have also demonstrated activity in relation to certain cancers (Melatoninxe2x80x94Clinical Perspectives, Oxford University, Press, 1988, pp. 164-165), ovulation (Science 1987, 227, pp. 714-720), diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).
Those various effects are exerted via the intermediary of specific melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible, for various species, including mammals, for some of those receptors to be located and characterised. In order to be able to understand the physiological functions of those receptors better, it is of great advantage to have available specific ligands. Moreover, such compounds, by interacting selectively with one or other of those receptors, may be excellent medicaments for the clinician in the treatment of pathologies associated with the melatoninergic system, some of which have been mentioned above.
In addition to the fact that the compounds of the present invention are new, they show very strong affinity for melatonin receptors and/or selectivity for one or other of the melatoninergic binding sites.
More especially, the present invention relates to compounds of formula (I): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2. 
xe2x80x83or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2. Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)-cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group 10 in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms, optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore). or G1 represents an alkylene chain having from 1 to 4 carbon atoms in which one of CH2 group can be replaced by a cycloalkylene (C3-C8) group,
A represents a group 
xe2x80x83wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen.
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group,
xe2x80x83or R2 and R3 together form an oxo group,
xe2x80x94R4 and R1 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol  means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An advantageous variant of the present invention relates to compounds of formula (1): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2, 
xe2x80x83or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)xe2x80x94 cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms, optionally substituted by a group R, OR, COR or COOR (wherein R is as defined hereinbefore).
A represents a group 
xe2x80x83wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore,
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen,
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group, or R and R together form an oxo group,
R4 and R5 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol  means that the bond may be single or double, with the proviso that the valence of the atoms is respected,
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d, xe2x80x9ccycloalkylxe2x80x9d, xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms.
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
An another advantageous variant of the present invention relates to compounds of formula (I): 
wherein:
the symbol 
xe2x80x83represents the grouping 
R1 represents a halogen atom or a group xe2x80x94R, xe2x80x94OR, xe2x80x94S(O)nR, xe2x80x94NRRxe2x80x2, 
xe2x80x83or xe2x80x94SO2NRRxe2x80x2 (wherein n is 0, 1 or 2, Z represents a sulphur or oxygen atom, and R, Rxe2x80x2 and Rxe2x80x3, which may be identical or different, represent a hydrogen atom or an unsubstituted or substituted linear or branched (C1-C6)alkyl group, an unsubstituted or substituted linear or branched (C2-C6)alkenyl group, an unsubstituted or substituted linear or branched (C2-C6)alkynyl group, an unsubstituted or substituted (C3-C8)-cycloalkyl group, an unsubstituted or substituted (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a heteroaryl group or a heteroaryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, it also being possible for (R and Rxe2x80x2) and (Rxe2x80x2 and Rxe2x80x3) to form together with the nitrogen atom carrying them a morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl group, those groups being unsubstituted or substituted),
G1 represents an alkylene chain having from 1 to 4 carbon atoms in which one of CH2 group can be replaced by a cycloalkylene (C3-C8) group,
A represents a group 
xe2x80x83wherein R, Rxe2x80x2, Rxe2x80x3 and Z are as defined hereinbefore.
B forms with the nitrogen atom and the carbon atom to which it is attached a ring having from 5 to 8 ring members, which may contain one or more unsaturated bonds and may contain, in addition to the nitrogen atom, an additional hetero atom selected from oxygen, sulphur and nitrogen,
R2 and R3, which may be identical or different, represent a hydrogen atom or a linear or branched (C1-C6)alkyl group, a linear or branched (C1-C6)alkoxy group or a hydroxy group,
xe2x80x83or R2 and R3 together form an oxo group,
R4 and R5 represent a hydrogen atom or form together with two adjacent atoms of the B ring carrying them a group selected from aryl and heteroaryl,
the symbol  means that the bond may be single or double, with the proviso that the valence of the atoms is respected.
it being understood that:
the term xe2x80x9csubstitutedxe2x80x9d applied to the terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkenylxe2x80x9d, xe2x80x9calkynylxe2x80x9d. xe2x80x9ccycloalkylxe2x80x9d.
xe2x80x9cmorpholinylxe2x80x9d, xe2x80x9cpiperidinylxe2x80x9d, xe2x80x9cpiperazinylxe2x80x9d and xe2x80x9cpyrrolidinylxe2x80x9d means that those groups may be substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
the term xe2x80x9csubstitutedxe2x80x9d applied to the term xe2x80x9ccycloalkylalkylxe2x80x9d means that the cyclic moiety of the group is substituted by one or more groups selected from hydroxy, oxo, alkoxy, alkyl, polyhaloalkyl, and halogen atoms,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl or biphenyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, alkoxycarbonyl, amido, and halogen atoms,
xe2x80x9cheteroarylxe2x80x9d is understood to mean a furyl, pyrrolyl, imidazolyl, pyridyl, thienyl, pyrazinyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, quinolyl or quinazolinyl group, those groups being unsubstituted or substituted by one or more identical or different groups selected from hydroxy, alkoxy, alkyl, amino, alkylamino, dialkylamino, nitro, cyano, polyhaloalkyl, formyl, carboxy, amido, and halogen atoms,
their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
The preferred compounds of the invention are the compounds of formula (1) wherein B forms with the nitrogen atom and the carbon atom to which it is attached a pyrrolidine ring, a piperidine ring, a (perhydro)azepine ring (7 ring members), a (perhydro)azocine ring (8 ring members) or a ring containing in addition to the nitrogen atom an oxygen atom, and more preferably a 1,3-(perhydro)oxazine ring.
The preferred groups R2 and R3 of the compounds of formula (I) are the hydrogen atom
The preferred groups R4 and R5 of the compounds of formula (I) are the hydrogen atom or when R4 and R5, carried by two adjacent atoms of the B ring, form with those two atoms an unsubstituted or substituted phenyl group.
The invention relates more especially to the compounds of formula (I) wherein R1 represents a group OR and more preferably a group OR wherein R represents a hydrogen atom or a linear or branched (C1-C6)alkyl group, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or tert-butyl.
The preferred group G1 of the compounds of formula (I) is the group (CH2)p wherein p is 2 or 3 and more preferably 2.
Advantageously, the invention relates to compounds of formula (I) wherein A represents a group NHCOR or CONHR and more especially a group NHCOR or CONHR wherein R represents a linear or branched (C1-C6)alkyl group, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or tert-butyl, a (C3-C8)cycloalkyl group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a (C3-C8)cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, such as, for example, cyclopropylmethyl, cyclobutylmethyl or cyclohexylmethyl, an aryl group, such as, for example, phenyl, iodophenyl, trifluoromethylphenyl or methoxyphenyl, an aryl-(C1-C6)xe2x80x94 alkyl group in which the alkyl moiety is linear or branched, such as, for example, benzyl, or a heteroaryl group, such as, for example, furyl, thienyl, pyrrolyl, pyridyl or indolyl.
The invention relates most especially to the compounds of formula (I) that are
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]acetamide,
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]-2-furamide,
N-[2-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)ethyl]benzamide,
N-[2-(3-methoxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)ethyl]acetamide,
N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]-2-furamide,
N-[2-(2-methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethyl]acetamide,
N-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)-ethyl]acetamide,
N-[2-(8-methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)-ethyl]-2-furamide,
N-[2-(10-methoxy-5,6-dihydropyrido[2xe2x80x2,3:4,5]pyrrolo[2,1-a]isoquinolin-12-yl)-ethyl]-2-furamide,
N-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4.5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]acetamide,
N-[2-(11-methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]-2-furamide,
N-[2-(11-hydroxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]benzazepin-13-yl)ethyl]-2-furamide.
The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein W represents a radical of formula (III): 
wherein R1, R2, R3, R4, R5, B, the symbol 
and the symbol  are
as defined hereinbefore,
which is subjected to
the action of a reducing agent to obtain a compound of formula (IV):
Wxe2x80x94CH2OHxe2x80x83xe2x80x83(IV) 
xe2x80x83wherein W is as defined hereinbefore.
xe2x80x83which, after conversion to the corresponding halogen compound, is subjected to the action of a cyanide salt to yield a compound of formula (V)
Wxe2x80x94CH2xe2x80x94CNxe2x80x83xe2x80x83(V) 
xe2x80x83wherein W is as defined hereinbefore
xe2x80x83or, in succession, a Wittig reaction and then reduction to obtain a compound of formula (VI):
Wxe2x80x94Gxe2x80x21xe2x80x94Xxe2x80x83xe2x80x83(VI) 
xe2x80x83wherein W is as defined hereinbefore, X represents a group CN or COOalk (wherein alk represents an alkyl group) and Gxe2x80x21 represents a chain as defined hereinbefore for G1 having from 2 to 4 carbon atoms,
which compounds of formulae (V) and (VI) are hydrolysed in an acidic or basic medium to obtain a compound of formula (VII):
Wxe2x80x94G1xe2x80x94COOHxe2x80x83xe2x80x83(VII) 
wherein W and GI are as defined hereinbefore,
which is subjected, in the presence of a coupling agent or after conversion to the corresponding acid chloride, to the action of an amine HNRRxe2x80x2 wherein R and Rxe2x80x2 are as defined hereinbefore to yield a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein W, G1, R and Rxe2x80x2 are as defined hereinbefore,
which compound of formula (I/a), when R and Rxe2x80x2 simultaneously represent a hydrogen atom, is subjected to the action of NaOBr to yield, after hydrolysis, a compound of formula (VIII):
Wxe2x80x94G1xe2x80x94NH2xe2x80x83xe2x80x83(VIII) 
wherein W and GI are as defined hereinbefore,
which is subjected to the action of:
an acyl chloride of formula (IX): 
xe2x80x83wherein R is as defined hereinbefore, or the corresponding acid anhydride (mixed or symmetric),
xe2x80x83to obtain a compound of formula (I/b), a particular case of the compounds of formula (I): 
xe2x80x83wherein W, G1 and R are as defined hereinbefore,
xe2x80x83which compound of formula (I/b) may also be obtained, when G1 represents chain (CH2)2, starting from a compound of formula (II) by the action of nitromethane to yield a compound of formula (IIIxe2x80x2) 
xe2x80x83wherein W is as defined hereinbefore,
xe2x80x83which is subjected to the action of a reducing agent, such as NaBR4, for example, to obtain a compound of formula (IVxe2x80x2): 
xe2x80x83wherein W is as defined hereinbefore,
xe2x80x83which is subjected to catalytic hydrogenation to obtain a compound of formula (Vxe2x80x2) 
xe2x80x83wherein W is as defined hereinbefore,
xe2x80x83which is subjected to the action of an acid chloride of formula (IX) or the corresponding acid anhydride (mixed or symmetric) to obtain a compound of formula (I/bxe2x80x2), a particular case of the compounds of formula (I/b) 
xe2x80x83wherein W and R are as defined hereinbefore,
or which compound of formula (VIII) is subjected to the action of a compound of formula (X):
Oxe2x95x90Cxe2x95x90Nxe2x80x94Rxe2x80x83xe2x80x83(X) 
xe2x80x83wherein R is as defined hereinbefore,
xe2x80x83to yield a compound of formula (I/c), a particular case of the compounds of formula (1): 
xe2x80x83wherein W, G1 and R are as defined hereinbefore,
which compounds of formulae (I/b) and (I/c) may be subjected to the action of a compound of formula (XI):
Ra-Jxe2x80x83xe2x80x83(XI) 
wherein Ra can have any of the meanings of R with the exception of the hydrogen atom and J represents a leaving group, such as a halogen atom or a tosyl group,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein W, G1 and Ra are as defined hereinbefore and Y represents a group R or xe2x80x94NRRxe2x80x2 wherein R and Rxe2x80x2 are as defined hereinbefore,
and/or which compounds of formulae (I/a), (I/b), (I/c) and (I/d) may be subjected to the action of a thionisation agent, such as Lawesson""s reagent, to yield a compound of formula (I/e), a particular case of the compounds of formula (I):
Wxe2x80x94G1-Txe2x80x83xe2x80x83(I/e) 
wherein W and G1 are as defined hereinbefore and T represents a group 
or 
wherein R, Rxe2x80x2 and Y are as defined hereinbefore, which compounds (I/a) to (I/e) constitute the totality of the compounds of formula (I) and may be purified according to a conventional purification technique, are converted, if desired, into their addition salts with a pharmaceutically acceptable acid or base, and separated, where appropriate, into their isomers according to a conventional separation technique.
The compounds of formula (III) are either commercial products or are accessible to the person skilled in the art by conventional chemical reactions.
In particular, the compounds of formula (III) may be obtained starting from a compound of formula (XII): 
wherein R1 and the symbol 
are as defined hereinbefore,
which is either a commercial product or is obtained according to a procedure described by G. Guillaumet et al. (Heterocycles, 1999. 50 (2), pp. 1065-1079), which is condensed with a compound of formula (XIII):
Hal-G1-Halxe2x80x83xe2x80x83(XIII) 
wherein Hal represents a halogen atom and G, represents a chain containing from 3 to 6 ring members, substituted by the groups R2, R3, R4 and R5 as defined hereinbefore, that may contain one or more unsaturated bonds and optionally contains a hetero atom selected from oxygen, nitrogen and sulphur,
to yield a compound of formula (XIV): 
wherein R1, G2, Hal and the symbol 
are as defined hereinbefore,
which is converted, by the successive action of bromine in tBuOH and then zinc in acetic acid, to a compound of formula (XV): 
xe2x80x83wherein R1, G2, Hal and the symbol 
xe2x80x83are as defined hereinbefore
or formylated by the action of POCl3 in dimethylformamide (DMF) to yield a compound of formula (XVI): 
xe2x80x83wherein R1, G2, Hal and the symbol 
xe2x80x83are as defined hereinbefore,
xe2x80x83(it also being possible for the compound of formula (XVI) to be obtained starting from a compound of formula (XII), which is subjected in succession to formulation and then to condensation of the compound of formula (XIII)),
xe2x80x83which compound of formula (XVI) is placed in cyclisation conditions, such as Bu3SnH/AIBN, to yield a compound of formula (III).
xe2x80x83which compounds of formulae (XIV) and (XV) may also be subjected to cyclisation conditions using, depending upon the case, reagents such as, for example. NaH in DMF or (PPh3)4 Pd, to yield a compound of formula (XVII): 
xe2x80x83wherein R1, R2, R3, R4, R5, B and the symbol 
xe2x80x83are as defined hereinbefore.
xe2x80x83which is subjected to formylation conditions, such as POCl3 in DMF, to obtain a compound of formula (III).
The present invention relates also to compounds of formula (XVII) as defined hereinbefore for use as intermediates in the synthesis of compounds of formula (I).
The compounds of the invention and the pharmaceutical compositions containing them have proved to be useful in the treatment of disorders of the melatoninergic system.
Pharmacological study of the compounds of the invention has in fact shown that they are atoxic, have a very high affinity for melatonin receptors and have substantial activities in respect of the central nervous system, and, in particular, therapeutic properties in respect of sleep disorders, anxiolytic, antipsychotic and analgesic properties, as well as properties in respect of microcirculation have been found, enabling it to be established that the compounds of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal affective disorder, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson""s disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, Alzheimer""s disease, and in cerebral circulation disorders. In another field of activity, it appears that the compounds of the invention can be used in the treatment of sexual dysfunctions, that they have ovulation-inhibiting and immunomodulating properties and are capable of being used in the treatment of cancers.
The compounds will preferably be used in the treatment of seasonal affective disorder, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to jetlag, appetite disorders and obesity.
For example, the compounds will be used in the treatment of seasonal affective disorder and sleep disorders.
The present invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) on its own or in combination with one or more pharmaceutically acceptable excipients.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration and especially tablets or dragees, sublingual tablets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way. The following Preparations yield synthesis intermediates for use in the preparation of the compounds of the invention.
Preparation 1: 2-(2-Methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)-ethylamine
Step A: 2-(6-Methoxy-3-nitro-2-pyridinyl)acetonitrile
Under argon and in an anhydrous medium, 15 g (97.3 mmol) of 2-methoxy-5-nitropyridine and 17.9 g (107 mmol) of 4-chlorophenoxyacetonitrile are dissolved in 300 ml of anhydrous tetrahydrofuran; the solution is added by transfer to a solution of 24 g (214 mmol) of potassium tert-butylate in 220 ml of anhydrous tetrahydrofuran maintained at a temperature below xe2x88x9210xc2x0 C. The reaction mixture is stirred for three hours at a temperature of from xe2x88x9210 to xe2x88x9215xc2x0 C. An aqueous 5% hydrochloric acid solution (170 ml) is added dropwise to the reaction mixture, maintaining the temperature at xe2x80x9410xc2x0 C. The mixture is extracted with ethyl acetate. After driving over magnesium sulphate and evaporation, the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 2:1). After washing with a petroleum ether/diethyl ether mixture (2:1), the title compound is obtained in the form of a brown product.
Melting Point: 116-117xc2x0 C.
Step B. 5-Methoxy-1H-pyrrolo[3,2-b]pyridine
Under a hydrogen pressure of 45 psi. 17.70 g (91.7 mmol) of the compound obtained in Step A and 2.5 g of palladium-on-carbon suspended in 300 ml of ethanol are stirred for 5 hours at room temperature. After filtration over Celite and evaporation, the residue is purified over silica gel (eluant:petroleum ether/ethyl acetate, 4:1) to yield the title product in the form of a brown solid.
Melting Point: 111-112xc2x0 C.
Step C: 1-(2-Bromobenyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine
Under argon and in an anhydrous medium, 590 mg (14.75 mmol) of sodium hydride (60% in oil) are added slowly to a solution of 1.81 g (12.23 mmol) of the compound obtained in Step B in 50 ml of N,N-dimethylformamide at 0xc2x0 C. After 30 minutes"" stirring at room temperature, 2.27 ml (14.75 mmol) of 2-bromobenzyl bromide in 15 ml of N,N-dimethylformamide are added dropwise to the reaction mixture. Stirring is maintained at room temperature under argon for two hours. After hydrolysis and then extraction with ethyl acetate, the organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a brown solid.
Melting point: 86-87xc2x0 C.
Step D: 2-Methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2, 1-a]isoindole
Under an inert atmosphere, 500 mg (1.57 mmol) of the compound obtained in Step C, 88 mg (78.9 xcexcmol) of tetrakis(triphenylphosphine)palladium (0) and 155 mg (1.57 mmol) of potassium acetate in 15 ml of N,N-dimethylacetamide are heated at 160xc2x0 C., for 2 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a brown solid.
Melting point: 192-193xc2x0 C.
Step E: 2-Methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindole-11-carbaldehyde
Under argon and in an anhydrous medium 291 xcexcl (3.17 mmol) of phosphorus oxychloride are added dropwise to 6 ml of N,N-dimethylformamide maintained at 0xc2x0 C.; after 15 minutes"" stirring, 500 mg (2.1 l mmol) of the compound obtained in Step D dissolved in 10 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0xc2x0 C., and then for 2 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water: the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a brown solid.
Melting point: 229-230xc2x0 C.
Step F: 2-Methoxy-11-[2-nitroethenyl]-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]-isoindole
600 mg (2.27 mmol) of the compound obtained in Step E dissolved in 25 ml of nitromethane are heated at 120xc2x0 C., for 3 hours in the presence of 440 mg (5.67 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Melting point: 197-198xc2x0 C.
Step G: [2-Methoxy-]-(2-nitroethyl)-6H-pyrido[2,3xe2x80x2:4,5]pyrrolo[2,1-a]-isoindole
Under argon and in an anhydrous medium, 660 mg (2.15 mmol) of the compound obtained in Step F are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 408 mg (10.75 mmol) of sodium borohydride are added slowly. After 30 minutes"" stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Melting point: 127-128xc2x0 C.
Step H: 2-(2-Methoxy-3H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)-ethylamine
Under a hydrogen pressure of 55 psi. 530 mg (1.71 mmol) of the compound obtained in Step G and 210 mg of Raney nickel are stirred in 20 ml of methanol at 60xc2x0 C., for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to yield the title amine in the form of a brown oil.
Melting point (oxalate): 149-150xc2x0 C.
Preparation 2: 2-[2-Methoxy-8-(trifluoromethyl)-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]-isoindol-11-yl]ethylamine
The procedure is as for Preparation 1, in Step C replacing 2-bromobenzyl bromide by (4-trifluoromethyl)-2-bromobenzyl bromide.
Preparation 3: 4-(2-Methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl]-butanoic Acid
Step A: Ethyl4-(2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)-3-butenoate
10.7 mmol of the compound obtained in Step E of Preparation 1 in 20 ml of anhydrous THF are placed in the presence of 1.2 eq of NaH (60% in oil) in 25 ml of anhydrous THF and of 1.2 eq of ethyl 3-(diethoxyphosphoryl)propanoate. The title compound is obtained after 3 hours"" stirring at room temperature and gentle refluxing overnight.
Step B: 4-(2-Methoxy,-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-11-yl)-butanoic Acid
The ester obtained in Step A is placed in 150 ml of ethanol in the presence of 40 ml of 2 N sodium hydroxide solution. The title acid is isolated after stirring at room temperature and then refluxing.
Preparation 4: 2-(10-Methoxy-5,6-dihydropyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]-isoquinolin-12-yl)ethylamine
Step A: 1-{[2-(2-Bromophenyl)-1,3-dioxolan-2-yl]methyl}-5-methoxy-1H-pyrrolo[3,2-b]pyridine
Under argon and in an anhydrous medium, 295 mg (2.6 mmol) of potassium tert-butylate are added to a solution containing 300 mg (2 mmol) of the compound obtained in Step B of Preparation 1 and 785 mg (2.4 mmol) of 2-(bromoethyl)-2-(2-bromophenyl)-1,3-dioxolane in 5 ml of dimethyl sulphoxide. The reaction mixture is heated at 100xc2x0 C., for 24 hours. After returning to room temperature, the mixture is hydrolysed with water and then extracted with ethyl acetate. After washing several times with water, the organic phase is dried over magnesium sulphate, filtered and then evaporated. Purification by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 85:15) yields the title compound in the form of a white solid.
Melting point: 143-144xc2x0 C.
Step B: 1-(2-Bromophenyl)-2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-ethanone
A solution containing 1.60 g (4.1 mmol) of the compound obtained in Step A in 10 ml of methanol and 20 ml of 18% hydrochloric acid is refluxed for 4 hours. After returning to room temperature and removal of the methanol by evaporation, the mixture is neutralised with a saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a white solid.
Melting point: 116-117xc2x0 C.
Step C: 1-(2-Bromophenethyl)5-methoxy-1H-pyrrolo[3,2-b pyridine
140 xcexcl (2.9 mmol) of hydrazine hydrate and 80 mg (2 mmol) of sodium hydroxide are added to a solution of 200 mg (0.6 mmol) of the compound obtained in Step B in 2 ml of diethylene glycol. After 24 hours"" stirring at 160xc2x0 C., the mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and then purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3) to yield the title compound in the form of a yellow oil.
Step D: 10-Methoxy-5,6-dihydropyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoquinoline
The title compound is obtained starting from the compound obtained in Step C according to the experimental protocol described in Step D of Preparation 1. Yellow solid.
Melting point: 179-180xc2x0 C.
Step E: 10-Methoxy-5,6-dihydropyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoquinoline-12-carbaldehyde
The same procedure is used as in Step E of Preparation 1. Yellow solid.
Melting point: 192-193xc2x0 C.
Step F: 2-(10-Methoxy-5,6-dihydropyrido[2xe2x80x2,3xe2x80x2:4, 5]pyrrolo[2,1-a]-isoquinolin-12-yl)ethylamine
The procedure is as for Steps F, G and H of Preparation 1. Brown oil.
Melting point (oxalate): 137-138xc2x0 C.
Preparation 5: 2-(11-Methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]2]-benzazepin-13-yl)ethylamine
Step A: 1-[3-(2-Bromophenyl)propyl]-5-methoxy-1H-pyrrolo[3,2-b]pyridine
Under argon and in an anhydrous medium, 162 mg (4.05 mmol) of sodium hydride (60% in oil) are added slowly, at 0xc2x0 C., to a solution of 500 mg (3.38 mmol) of the compound obtained in Step B of Preparation 1 in 10 ml of N,N-dimethylformamide. After 35 minutes"" stirring at room temperature, a solution of 1.3 g (4.05 mmol) of 1-bromo-2-(3-iodopropyl)-benzene dissolved in 5 ml of N,N-dimethylformamide is added to the mixture. After 1 hour""s stirring at room temperature, the mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) to yield the title compound in the form of a yellow oil.
Step B: 11-Methoxy-6,7-dihydro-5H-pyrido[2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]-benzazepine
Under an inert atmosphere, 500 mg (1.45 mmol) of the compound obtained in Step A, 81 mg (72.5 xcexcmol) of tetrakis(triphenylphosphine)palladium (0) and 142 mg (1.45 mmol) of potassium acetate in 15 ml of N,N-dimethylacetamide are heated at 160xc2x0 C., for 2 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 9:1) to yield the title compound in the form of a colourless oil.
Step C: 11-Methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]-benzazepine-13-carbaldehyde
The procedure is as for Step F of Preparation 1.
Step D 2-(11-Methoxy-6,7-dihydro-5H-pyrido[2xe2x80x2, 3xe2x80x2:4,5]pyrrolo[2,1-a][2]-benzazepin-13-yl)ethylamine
The procedure is as for Steps G and H of Preparation 1. Green solid.
Melting point: 114-115xc2x0 C.
Preparation 6: 4-(6,7-Dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]-benzazepin-13-yl)butanoic Acid
The procedure is as for Preparation 3 starting from 6.7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4.5]pyrrolo[2,1-a][2]benzazepine-13-carbaldehyde (obtained according to a process analogous to Steps A, B and C of Preparation 5).
Preparation 7: 2-(11-Ethyl-6,7-dihydro-5H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a][2]-benzazepin-13-yl)ethylamine
The procedure is as for Preparation 5 starting from 2-ethyl-5-nitropyridine.
Preparation 8: 2-(2-Methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethylamine
Step A: 1-(4-Bromobutyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine
Under argon and in an anhydrous medium, 810 mg (20.27 mmol) of sodium hydride (60% in oil) are added slowly to a solution of 2 g (13.51 mmol) of the compound obtained in Step B of Preparation 1 in 30 ml of N,N-dimethylformamide at 0xc2x0 C. After stirring for one hour at room temperature, the solution containing the previously formed anion is added dropwise to 4.8 ml (40.54 mmol) of 1,4-dibromobutane. After stirring for two hours at room temperature the reaction mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate. 8:2) to yield the title compound in the form of a colourless oil
Step B: 1-(4-Bromobutyl)-5-methoxy-1H-pyrrolo[3, 2-b]pyridine-3-carbaldehyde
Under argon and in an anhydrous medium, 730 II (7.95 mmol) of phosphorus oxychloride are added dropwise to 12.5 ml of N,N-dimethylformamide maintained at 0xc2x0 C.; after 30 minutes"" stirring, 1.50 g (5.3 mmol) of the compound obtained in Step A dissolved in 25 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0xc2x0 C., and then for 3 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water; the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a yellow oil.
Step C: 2-Methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizine-10-carbaldehyde
Under argon, a solution containing 2.70 g (8.67 mmol) of the compound obtained in Step B and 1.45 g (8.67 mmol) of AIBN in 80 ml of toluene is brought to reflux. After stirring for 20 minutes, 4.67 ml (17.35 mmol) of tributyltin hydride in 100 ml of toluene are added to the reaction mixture, which is maintained at reflux for 24 hours. After returning to room temperature and evaporation to dryness, the residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 95:5) to yield the title product in the form of a yellow oil.
Step D: 2-Methoxy-10-[2-nitroethenyl]-6,7,8,9-tetrahydropyrido[2,3-b]indolizine
550 mg (2.39 mmol) of the compound obtained in Step C dissolved in 25 ml of nitromethane are heated at 120xc2x0 C., for 3 hours in the presence of 460 mg (5.97 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. After washing with a pentane/diethyl ether mixture, the title compound is obtained in the form of a brown solid.
Melting point: 202-203xc2x0 C.
Step E: 2-Methoxy-10-(2-nitroethyl)-6,7,8,9-tetrahydropyrido[2,3-b]indolizine
Under argon and in an anhydrous medium, 650 mg (2.38 mmol) of the compound obtained in Step D are suspended in 10 ml of isopropanol and 30 ml of chloroform in the presence of 1.5 g of 230-400 mesh silica; 450 mg (11.90 mmol) of sodium borohydride are added slowly. After stirring for 30 minutes at room temperature, acetic acid is added and the reaction mixture is filtered over a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered and concentrated to yield the title compound in the form of a yellow solid.
Melting point: 96-97xc2x0 C.
Step F: 2-(2-Methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)ethylamine
Under a hydrogen pressure of 55 psi, 420 mg (1.53 mmol) of the compound obtained in Step E and 170 mg of Raney nickel are stirred in 20 ml of methanol at 60xc2x0 C., for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to yield the title product in the form of a brown oil.
Preparation 9: 2-(3-Methoxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)ethylamine
Step A: 3,3,5-Tribromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one
At room temperature. 54 ml (1.05 mol) of bromine are added dropwise to 10 g (84 mmol) of 7-azaindole dissolved in 660 ml of tert-butanol and 660 ml of water. After 19 hours"" stirring at room temperature, the tert-butanol is removed by evaporation and the residual aqueous phase is rendered alkaline with an aqueous saturated sodium hydrogen carbonate solution. The desired product is recovered by filtration. After drying in vacuo in the presence of phosphorus pentoxide, the title compound is obtained in the form of a brown oil.
Melting point: 157-158xc2x0 C.
Step B: 5-Bromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one
Under argon at room temperature, 17.60 g (0.27 mol) of powdered zinc are added in portions to 5 g (13.5 mmol) of the compound obtained in Step A dissolved in 100 ml of acetic acid. After 15 hours"" stirring at room temperature, the acetic acid is removed by evaporation under reduced pressure (coevaporation with toluene). The residue, which is taken up in ethyl acetate, is washed once with water; the aqueous phase is washed several times with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:dichloromethane/methanol, 95/5), to obtain the title compound in the form of an orange solid.
Melting point: 250-251xc2x0 C.
Step C: 5-Bromo-1H-pyrrolo[2,3-b]pyridine
Under an argon atmosphere and in an anhydrous medium, 37.6 ml (37.6 mmol) of a 1 M solution of borane-tetrahydrofuran complex in tetrahydrofuran are added at 0xc2x0 C., and dropwise to a suspension of 2 g (9.4 mmol) of the compound obtained in Step B in 50 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 35 minutes at room temperature and then evaporated to dryness. The residue is taken up in an aqueous 6 M hydrochloric acid solution and heated until the solid has completely dissolved. After cooling, the solution is rendered alkaline with an aqueous 6 M sodium hydroxide solution and extracted with ethyl acetate. After drying over magnesium sulphate and evaporation, an equimolar mixture of 5-bromo-7-azaindoline and 5-bromo-7-azaindole is obtained. The preceding residue, which is dissolved in 20 ml of acetic acid, is added at room temperature to a suspension of 4.10 g (15.3 mmol) manganese (III) acetate dihydrate in 20 ml of acetic acid. After 45 minutes"" stirring at 75xc2x0 C., the solution is evaporated to dryness and coevaporated with toluene. The residue, which is taken up in water, is rendered alkaline with an aqueous saturated sodium hydrogen carbonate solution. After extraction with ethyl acetate, the organic phases are dried over magnesium sulphate and evaporated. The resulting residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound in the form of a yellow solid.
Melting point: 176-177xc2x0 C.
Step D: 5-Methoxy-1H-pyrrolo[2,3-b]pyridine
Under an argon atmosphere and in an anhydrous medium, 1 g (5.07 mmol) of the compound obtained in Step C is dissolved in a mixture of 25 ml of N,N-dimethylformamide and 22 ml of methanol; 6.86 g (126.75 mmol) of sodium methanolate and 1.43 g (10.30 mmol) of copper (I) bromide are added at room temperature. The mixture is heated at reflux for 3 hours. After removal of the solvents by evaporation, the residue is taken up in water and ethyl acetate and then filtered over Celite. The organic phase is washed with water, dried over magnesium sulphate and evaporated to yield a solid, which is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3). The title compound is obtained in the form of a brown solid.
Melting point: 162-163xc2x0 C.
Step E: 2-(3-Methoxy-6,7,8,9-tetrahydropyrido[3,2-b]indolizin-5-yl)ethylamine
The procedure is as for A, B, C, D, E and F of Preparation 8 starting from the compound obtained in Step D. Brown oil.
Preparation 10: 4-(2-Methoxy-6,7,8,9-tetrahydropyrido[2,3-b]indolizin-10-yl)butanoic Acid
The procedure is as for Preparation 3 starting from the compound obtained in Step C of Preparation 8.
Preparation 11: 2-(2-Methoxy-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizin-9-yl)-ethylamine
The procedure is as for Preparation 8, in Step A replacing 1,4-dibromobutane by 1.4-dibromopropane.
Preparation 12: 2-(2-Isopropyl-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizin-9-yl)-ethylamine
The procedure is as for Preparation 8, in Step A replacing 5-methoxy-1H-pyrrolo[3,2-b]-pyridine by 5-isopropyl-1H-pyrrolo[3,2-b]pyridine and 1,4-dibromobutane by 1,3-dibromopropane.
Preparation 13: 2-[2-(Benzyloxy)-7,8,9,10-tetrahydro-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo-[1,2-a]azepin-11-yl]ethylamine
The procedure is as for Preparation 8, in Step A replacing 5-methoxy-1H-pyrrolo[3,2-b]-pyridine by 5-benzyloxy-1H-pyrrolo[3,2-b]pyridine and 1,4-dibromobutane by 1,5-dibromopentane.
Preparation 14: 2-(8-Methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]-oxazin-10-yl)ethylamine
Step A: 1-[3-(Benzyloxy)propyl]-5-methoxy-1H-pyrrolo[3, 2-b]pyridine
Under argon and in an anhydrous medium, 973 mg of sodium hydride (60% in oil) (24.32 mmol) are added slowly, at 0xc2x0 C., to a solution of 3 g (20.27 mmol) of the compound obtained in Step B of Preparation 1 in 90 ml of N,N-dimethylformamide. After 45 minutes"" stirring at room temperature, a solution of 4.3 ml (24.32 mmol) of 1-benzyloxy-3-bromopropane dissolved in 10 ml of N,N-dimethylformamide is added to the mixture. After 2 hours"" stirring at room temperature, the mixture is hydrolysed and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate. 7:3) to yield the title compound in the form of a yellow oil.
Step B: 1-[3-(Benzyloxy)propyl]-3,3-dibromo-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one
At room temperature, 1.74 ml (33.78 mmol) of bromine are added dropwise to 2 g (6.75 mmol) of the compound obtained in Step A dissolved in 55 ml of tert-butanol and 55 ml of water. After 10 hours"" stirring at room temperature, the tert-butanol is removed by evaporation and the residual aqueous phase is rendered alkaline with an aqueous saturated sodium hydrogen carbonate solution and then extracted with dichloromethane. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 9:1) to yield the title compound in the form of a brown oil.
Step C: 1-[3-(Benzyloxy)propyl]-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]-pyridin-2-one
Under argon and at room temperature, 1.10 g (16.8 mmol) of powdered zinc are added in portions to 789 mg (1.68 mmol) of the compound obtained in Step B dissolved in 15 ml of acetic acid. After 5 hours"" stirring at room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel, evaporated to dryness and then coevaporated in the presence of toluene. The residue, which is taken up in ethyl acetate, is washed several times with water. The organic phase is dried over magnesium sulphate, filtered and concentrated and then purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate. 1:1) to yield the title compound in the form of an orange oil.
Step D: 1-(3-Hydroxypropyl)-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one
Under a hydrogen pressure of 45 psi. 510 mg (1.63 mmol) of the compound obtained in Step C and 72 mg of palladium-on-carbon suspended in 10 ml of methanol are stirred for 15 hours at room temperature. After filtration over Celite and evaporation, the residue is hydrolysed with water and then extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated to yield the title compound in the form of a brown solid.
Melting point: 121-122xc2x0 C.
Step E: 1-(3-Bromopropyl)-5-methoxy-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one
Under argon and in an anhydrous medium, 1.50 g (3.76 mmol) of 1.2-bis-diphenylphosphinoethane are added at 0xc2x0 C., to a solution of 1.25 g (3.76 mmol) of carbon tetrabromide in 20 ml of dichloromethane. After 10 minutes at 0xc2x0 C., 417 mg (1.88 mmol) of the compound obtained in Step D dissolved in 10 ml of dichloromethane are added to the mixture. The mixture is stirred for 30 minutes at 0xc2x0 C., and then for 3 hours at room temperature. After hydrolysis of the reaction mixture, the organic phase is dried over magnesium sulphate, filtered and concentrated. Purification by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 8:2) yields the title compound in the form of a white solid.
Melting point: 82-83xc2x0 C.
Step F: 8-Methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazine
Under an inert atmosphere, 160 mg (4 mmol) of sodium hydride (60% in oil) are added slowly at 0xc2x0 C., to a solution of 380 mg (1.34 mmol) of the compound obtained in Step E in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at 0xc2x0 C., for 30 minutes before being hydrolysed with ice and then extracted with ethyl acetate. The organic phase is washed several times with water, dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether, 95:5) to yield the title compound in the form of a brown solid.
Melting point: 92-93xc2x0 C.
Step G: 8-Methoxy-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]oxazine-10-carbaldehyde
Under argon and in an anhydrous medium, 216 xcexcl (2.35 mmol) of phosphorus oxychloride are added dropwise to 3.5 ml of 1N-[-dimethylformamide maintained at 0xc2x0 C., after 15 minutes"" stirring, 320 mg (1.56 mmol) of the compound obtained in Step G dissolved in 5 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0xc2x0 C., and then for 2 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water; the aqueous phase is rendered alkaline with a 6 N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to yield the title compound in the form of a brown solid.
Melting point: 224-225xc2x0 C.
Step H: 8-Methoxy-10-[2-nitroethenyl]-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]-pyrrolo[2,1-b][1,3]oxazine
300 mg (1.29 mmol) of the compound obtained in Step G dissolved in 15 ml of nitromethane are heated at 120xc2x0 C., for 4 hours in the presence of 250 mg (3.23 mmol) of ammonium acetate. After returning to room temperature and evaporation to dryness, the reaction mixture is diluted in dichloromethane and washed with water. After drying over magnesium sulphate, evaporation of the organic phase yields the title compound in the form of a yellow solid.
Melting point: 248-249xc2x0 C.
Step I: 8-Methoxy-10-(2-nitroethyl)-3,4-dihydro-2H-pyrido[2xe2x80x2,3xe2x80x2:4,5]-pyrrolo[2,1-b][1,3]oxazine
Under argon and in an anhydrous medium, 340 mg (1.23 mmol) of the compound obtained in Step H are suspended in 7 ml of isopropanol and 21 ml of chloroform in the presence of 810 mg of 230-400 mesh silica: 234 mg (6.18 mmol) of sodium borohydride are added slowly. After 2 hours"" stirring at room temperature, acetic acid is added and the reaction mixture is filtered through a glass frit. After removal of the solvents by evaporation, the residue is diluted in dichloromethane and washed with water. The organic phase is then dried over magnesium sulphate, filtered, concentrated and purified by flash chromatography over silica gel (eluant:ethyl acetate/petroleum ether. 6:4) to yield the title compound in the form of a yellow solid.
Melting point: 104-105xc2x0 C.
Step J: 2-(8-Methoxy-3,4-dihydro-2H-pyrido[2,3xe2x80x2,4,5]pyrrolo[2,1-b][1,3]-oxazin-10-yl)ethylamine
Under a hydrogen pressure of 55 psi, 410 mg (1.48 mmol) of the compound obtained in Step I and 165 mg of Raney nickel are stirred in 20 ml of methanol at 60xc2x0 C., for 15 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to yield the title amine in the form of a brown oil.
Melting point (oxalate): 84-85xc2x0 C.
Preparation 15: 2-(8-Methoxy-3,4-dihydro-2H-pyrido[4xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-b][1,3]-oxazin-10-yl)ethylamine
The procedure is as for Preparation 14 starting from 5-methoxy-1H-pyrrolo-[2.3-c]pyridine.
Preparation 16: 2-(2-Methoxy-6,7,8,9-tetrahydropyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo [2,1-b]-oxazepin-11-yl)ethylamine
The procedure is as for Preparation 14, in Step A replacing 1-benzyloxy-3-bromopropane by 1-benzyloxy-4-bromobutane.
Preparation 17: 2-(8-Methoxy-3,4-dihydro-2H-pyrido[3xe2x80x2,2xe2x80x2:4,5]pyrrolo[2,1-b][1,3]-oxazin-10-yl)ethylamine
Step A: 1-[3-(Benzyloxy)propyl]-5-bromo-1H-pyrrolo[2,3-b]pyridine
The procedure is as for Step A of Preparation 14 starting from the compound obtained in Step C of Preparation 9.
Step B: 1-[3-(Benzyloxy)propyl]-5-methoxy-1H-pyrrolo[2,3-b]pyridine
Under argon and in an anhydrous medium, 6.1 g (17.67 mmol) of the compound obtained in Step A are dissolved in a mixture of 115 ml of N,N-dimethylformamide and 110 ml of methanol; 24 g (0.44 mol) of sodium methanolate and 2.53 g (17.67 mmol) of copper (I) bromide are added at room temperature. The mixture is heated at reflux for 4 hours. After removal of the solvents by evaporation, the residue is taken up in ethyl acetate and filtered over Celite. The filtrate is washed with water. The organic phase is dried over magnesium sulphate, concentrated and purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate, 7:3) to yield the title compound in the form of a yellow oil.
Step C: 2-(8-Methoxy-3,4-dihydro-2H-pyrido[3xe2x80x2,2xe2x80x2:4,5]pyrrolo[2,1-b][1,3]-oxazin-10-yl)ethylamine
The procedure is as for Steps B, C, D, E, F, G, H, I and J of Preparation 14 starting from the compound obtained in Step B. Brown oil.
Preparation 18: 11-(2-Aminoethyl)-2-methoxy-6H-pyrido[2xe2x80x2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-6-one
Step A: 5-Methoxy-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde
The procedure is as for Step E of Preparation 1 from the compound obtained in Step B of Preparation 1.
Step B 1-(2-Iodobenzoyl)-5-methoxy-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde
Under an argon atmosphere, 0.56 mmol of the compound obtained in Step A are dissolved in 5 ml of DMF, and then 0.68 mmol of NaH are added at 0xc2x0 C., over a period of 30 minutes. After 30 minutes"" stirring at 0xc2x0 C., 0.68 mmol of 2-iodobenzoyl chloride dissolved in 5 ml of DMF is added dropwise to the mixture. After 3 hours"" stirring, the solvents are removed by evaporation and the residue is taken up in water and extracted with dichloromethane. After drying over magnesium sulphate and removal of the solvents by evaporation, the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound.
Step C: 2-Methoxy-6-oxo-6H-pyrido[2,3xe2x80x2:4,5]pyrrolo[2,1-a]isoindole-11-carbaldehyde
Under an argon atmosphere, 0.49 mmol of the compound obtained in Step B, 0.2 mmol of tetrakis(triphenylphosphine)palladium (0) and 0.49 mmol of potassium acetate in 15 ml of DMF are heated at 140xc2x0 C., for 3 hours. After returning to room temperature, the reaction mixture is filtered using a Bxc3xcchner funnel and then evaporated to dryness. The residue is then hydrolysed and subsequently extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated, and the residue is purified by flash chromatography over silica gel (eluant:petroleum ether/ethyl acetate) to yield the title compound.
Step D: 11-(2-Aminoethyl)-2-methoxy-6H-pyrido[2,3 xe2x80x2:4,5]pyrrolo[2,1-a]isoindol-6-one
The procedure is as for Steps F-H of Preparation 1.